The present invention relates to pharmaceutical compositions containing sulpiride compounds having the general formula:
where R1 is branched or straight chain alkyl having from 1 to about 7 carbon atoms, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted alkylcycloalkyl, or a group having the formula (CH2)n R2 where R2 is a substituted or unsubstituted aryl or a substituted or unsubstituted cycloalkyl, and n is an alkyl group having from 0 to about 6 carbon atoms.
Sulpiride is an atypical antipsychotic compound having antidepressant, antiemetic and prokinetic activity. Unlike other neuroleptic drugs, sulpiride is characterized by having a low incidence of extrapyramidal side effects. In particular, sulpiride is a substituted benzamide derivative that selectively inhibits dopamine D2 receptors in the chemoreceptor trigger zone of the central nervous system (CNS) and in the enteric nervous system of the gastrointestinal tract. Levosulpiride is the levorotatory (S) enantiomer of sulpiride. Levosulpiride, with antiemetic and prokinetic effects, acts selectively by blocking the D2 dopamine receptors in the CNS and in the peripheral submucosal and myenteric plexus of the gastrointestinal tract. The antiemetic effect of levosulpiride is due to inhibition of dopamine transmission and antagonism with D2 receptors of the neurons in the area postrema of the vomiting center (IV ventricle) or chemoreceptor trigger zone in the CNS, blocking the inhibitory effect of dopamine on cholinergic neurons and therefore permitting a sustained cholinergic induced contraction of smooth muscle cell in the myenteric plexus of the esophagus, stomach, gallbladder, and intestine.
The antiemetic and prokinetic effects of levosulpiride are unique, and permit the treatment of a larger number of gastrointestinal disorders than other drugs in its class. Gastric hypomotility with delayed emptying of liquid and/or solid contents is a component of a number of gastrointestinal disorders. The symptoms of such disorders may include nausea, vomiting, heartburn, postprandial discomfort, indigestion, and gastroesophageal reflux. Gallbladder emptying has been also linked to the rate at which food enters the proximal duodenum. Clinical trials have demonstrated efficacy for levosulpiride in patients for functional dyspepsia (indigestion with accompanying nausea, vomiting and heartburn), GERD (gastroesophageal reflux disease), postoperative and chemotherapy-induced nausea and vomiting; and gastroparesis (diabetic gastric stasis) in diabetics.
A particularly important therapeutic property of levosulpiride in the treatment of chemotherapy-induced nausea and vomiting is that the use of dexamethasone is not required for its efficacy. Current approved drugs used to treat both acute and delayed chemotherapy-induced nausea and vomiting require the addition of dexamethasone to the treatment regimen in order to achieve an acceptable clinical outcome. Injectable levosulpiride treatment of chemotherapy-induced nausea and vomiting results in clinically superior efficacy over currently approved emetic agents, without requiring dexamethasone. Wu et al. have reported that dexamethasone pretreatment of cancer cell lines significantly inhibits chemotherapy-induced apoptosis in a glucocorticoid receptor-dependent manner (Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, and Conzen SD, Cancer Research 64: 1757-1764 (2004)).
Despite its lack of side effects and its clinical efficacy without dexamethasone, the relative insolubility of levosulpiride in aqueous media has a significant impact on the formulation of both oral and parenteral dosage forms. Sulpiride is practically insoluble in water resulting in low absorption and bioavailability for the oral pharmaceutical formulations, and large injection volumes for the parenteral formulations. Moreover, because the pKa of levosulpiride is low, solubility in parenteral dosage forms requires the use of excipients having an extremely low pH. This, in turn, results in injectable products that have the potential to cause discomfort after injection to a patient.
Solubilization of water-insoluble drugs generally includes solubilization by pH control, by use of cosolvents, or by use of surfactants or complexation. The excipients used to solubilize drugs in oral and injectable dosage forms generally include pH modifiers, water-soluble organic solvents, water-insoluble organic solvents, surfactants and cyclodextrins.
Water-soluble drugs in oral dosage forms having a low molecular weight are normally well-absorbed as long as they are not degraded by the enzymes in the GI tract; however, many drugs are poorly soluble in water. Drugs which have a low solubility in water pose a tremendous challenge to pharmaceutical sciences. Adequate solubilization of such drugs with excipients which are biocompatible is a prerequisite to get the drug absorbed by the body after oral administration. After oral administration, these water-insoluble (lipophilic) drugs are confronted with the same uptake mechanisms as fatty components of food. They are solubilized by the bile juice, which contains phospholipids and bile salts which dissolve the lipophilic drugs in micellar structures. Incomplete or insufficient solubilization of drugs after oral administration often results in reduced absorption and corresponding reduced plasma bioavailability of the drug.
In the case of parenteral administration, these water-insoluble drugs usually contain co-solvents or adjustment of the carrier pH to solubilize the drug. These co-solvents and pH modifications can produce pain at the site of injection, or cause precipitation of drug at the site of administration that can have a marked effect on the blood concentration versus time profile.
For example, after intramuscular administration, the composition of the fluid in which the drug is dissolved is diluted by the fluid in the muscle, resulting in drug precipitating out at the site of injection. In order for absorption to take place, drug must redissolve through a slow process. As a consequence, administration of some drugs by the intramuscular route results in a slow release of drug from the site. If the dose administered is large enough, this can function as a sustained release preparation. However, if normal doses are given, the rise in drug concentration may be slowed to the degree that drug never achieves concentrations above the minimally effective concentration.
The currently available injectable formulation outside of the United States contains 25 mg of levosulpiride in 2 ml of water, sodium chloride and sulfuric acid. This formulation is generally administered at the following doses: 1 mg/kg iv (given 4-5 times) for chemotherapy-induced nausea and vomiting, and 50 to 100 mg iv for postsurgical nausea and vomiting.
The currently available oral formulation is a 25 mg tablet that is administered three times daily for a total daily dose of 75 mg/day for diabetic gastroparesis, GERD, and dyspepsia. Because sulpiride has limited aqueous solubility, the oral formulations suffer from a reduced absorption in the gastrointestinal tract (˜30%) and resultant low bioavailability. Because orally administered levosulpiride is absorbed predominantly from the upper part of the small intestine; the drug has a small absorption window in the gastrointestinal tract. Unless levosulpiride is taken with food, the transit time of levosulpiride along the upper portion of the small intestine reduces the opportunity for the drug to be absorbed from the effective site of absorption. A study in healthy volunteers has shown that the decreased emptying rate of sulpiride from the stomach after food permits more contact time between sulpiride and its absorption sites in the intestine, and increases absorption. Food was shown to increase the bioavailability in these subjects from 20 to 27%. Consequently, the drug is dosed three times daily with meals.
It is an object of the present invention to provide pharmaceutical compositions containing aryl and alkyl derivatives of sulpiride compounds having improved physiochemical properties.
It is a further object of the present invention to provide water-soluble aryl and alkyl derivatives of sulpiride and pharmaceutical compositions thereof.
It is a further object of the present invention to provide aryl and alkyl derivatives of sulpiride compounds having improved aqueous solubility over sulpiride.
It is a further object of the present invention to provide pharmaceutical compositions containing aryl and alkyl derivatives of sulpiride compounds having improved oral absorption of sulpiride in the upper portion of the small intestine.
It is a further object of the present invention to provide aryl and alkyl derivatives of sulpiride pharmaceutical compounds having improved injectable formulation properties.